WO2011018224A1 - Combination therapy of an afucosylated cd20 antibody with bendamustine - Google Patents

Combination therapy of an afucosylated cd20 antibody with bendamustine Download PDF

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Publication number
WO2011018224A1
WO2011018224A1 PCT/EP2010/004939 EP2010004939W WO2011018224A1 WO 2011018224 A1 WO2011018224 A1 WO 2011018224A1 EP 2010004939 W EP2010004939 W EP 2010004939W WO 2011018224 A1 WO2011018224 A1 WO 2011018224A1
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Prior art keywords
antibody
cancer
bendamustine
antibodies
afucosylated
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PCT/EP2010/004939
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English (en)
French (fr)
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Frank Herting
Christian Klein
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Roche Glycart Ag
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Priority to CN201080035971XA priority Critical patent/CN102596245A/zh
Priority to SG2012008843A priority patent/SG178324A1/en
Priority to AU2010281866A priority patent/AU2010281866B2/en
Priority to LTEP10747168.2T priority patent/LT2464382T/lt
Priority to SI201031491T priority patent/SI2464382T1/sl
Priority to DK10747168.2T priority patent/DK2464382T3/en
Priority to EP10747168.2A priority patent/EP2464382B1/en
Priority to BR112012002855A priority patent/BR112012002855A2/pt
Priority to NZ597666A priority patent/NZ597666A/xx
Priority to MA34585A priority patent/MA33469B1/fr
Priority to JP2012524146A priority patent/JP5646626B2/ja
Priority to ES10747168.2T priority patent/ES2630158T3/es
Priority to CA2769674A priority patent/CA2769674C/en
Application filed by Roche Glycart Ag filed Critical Roche Glycart Ag
Priority to MX2014015198A priority patent/MX355849B/es
Priority to RS20170647A priority patent/RS56146B1/sr
Priority to KR1020127006528A priority patent/KR101425736B1/ko
Priority to MX2012001782A priority patent/MX2012001782A/es
Priority to RU2012109445/15A priority patent/RU2575820C2/ru
Priority to UAA201202678A priority patent/UA110096C2/ru
Publication of WO2011018224A1 publication Critical patent/WO2011018224A1/en
Priority to IL217753A priority patent/IL217753A/en
Priority to ZA2012/00830A priority patent/ZA201200830B/en
Priority to HRP20170972TT priority patent/HRP20170972T1/hr
Priority to CY20171100706T priority patent/CY1119251T1/el
Priority to LU00045C priority patent/LUC00045I2/fr
Priority to NO2017054C priority patent/NO2017054I1/no
Priority to CY2017034C priority patent/CY2017034I2/el
Priority to LTPA2017035C priority patent/LTPA2017035I1/lt

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
    • C07K2317/41—Glycosylation, sialylation, or fucosylation

Definitions

  • the present invention is directed to the combination therapy of an afucosylated CD20 antibody with bendamustine for the treatment of cancer.
  • IgGl type antibodies the most commonly used antibodies in cancer immunotherapy, are glycoproteins that have a conserved N-linked glycosylation site at Asn297 in each CH2 domain.
  • the two complex biantennary oligosaccharides attached to Asn297 are buried between the CH2 domains, forming extensive contacts with the polypeptide backbone, and their presence is essential for the antibody to mediate effector functions such as antibody dependent cellular cytotoxicity (ADCC) (Lifely, M.
  • ADCC antibody dependent cellular cytotoxicity
  • the CD20 molecule (also called human B-lymphocyte-restricted differentiation antigen or Bp35) is a hydrophobic transmembrane protein located on pre-B and mature B lymphocytes that has been described extensively (Valentine, M.A., et al., J. Biol. Chem. 264 (1989) 11282-11287; and Einfeld, D.A., et al., EMBO J. 7
  • CD20 is expressed on greater than 90 % of B cell non-Hodgkin's lymphomas (NHL) (Anderson, K.C., et al., Blood 63 (1984) 1424- 1433)) but is not found on hematopoietic stem cells, pro-B cells, normal plasma cells, or other normal tissues (Tedder, T.F., et al., J, Immunol. 135(2) (1985) 973- 979).
  • NHL B cell non-Hodgkin's lymphomas
  • Type I antibodies as e.g. rituximab, are potent in complement mediated cytotoxicity
  • type II antibodies as e.g. Tosirumomab (Bl), 11B8, AT80 or humanized B-LyI antibodies
  • Bl Tosirumomab
  • 11B8 AT80
  • humanized B-LyI antibodies effectively initiate target cell death via caspase- independent apoptosis with concomitant phosphatidylserine exposure.
  • Table 1 The sharing common features of type I and type II anti-CD20 antibodies are summarized in Table 1.
  • Bendamustine (trade names Ribomustin and Treanda; also known as SDX- 105) is a nitrogen mustard used in the treatment of chronic lymphocytic leukemia (CLL)
  • the invention comprises the use of an afucosylated anti-CD20 antibody with an amount of fucose of 60 % or less of the total amount of oligosaccharides (sugars) at Asn297, for the manufacture of a medicament for the treatment of cancer in combination with bendamustine.
  • One aspect of the invention is a method of treatment of patient suffering from cancer by administering an afucosylated anti-CD20 antibody with an amount of fucose of 60 % or less of the total amount of oligosaccharides (sugars) at Asn297, in combination with bendamustine, to a patient in the need of such treatment.
  • Another aspect of the invention is an afucosylated anti-CD20 antibody with an amount of fucose of 60 % or less of the total amount of oligosaccharides (sugars) at Asn297, for the treatment of cancer in combination with bendamustine.
  • the amount of fucose is between 40 % and 60 % of the total amount of oligosaccharides (sugars) at Asn297.
  • the amount of fucose is 0% of the total amount of oligosaccharides at Asn297.
  • the afucosylated anti— CD20 antibody is an IgGl antibody.
  • said afucosylated anti-CD20 antibody is humanized B-LyI antibody, and said cancer is a CD20 expressing cancer, which in one embodiment is a B-CeIl Non-Hodgkin's lymphoma (NHL).
  • NDL B-CeIl Non-Hodgkin's lymphoma
  • the humanized B-LyI antibody is administered in a dosage of 800 to 1200 mg on day 1, 8, 15 of a 6-week-dosage-cycle and then in a dosage of 800 to 1200 mg on day 1 of up to five 4-week-dosage-cycles, and bendamustine is administered in a dosage of 80 mg/m2 to 110 mg/ m2 on day 1 and 2 of up to six 4- week-dosage-cycles .
  • One embodiment of the invention is a composition comprising an anti-CD20 afucosylated antibody with an amount of fucose of 60 % or less, and bendamustine for the treatment of cancer.
  • the invention comprises the use of an afucosylated anti-CD20 antibody of IgGl or
  • IgG3 isotype (preferably of IgGl isotype)with an amount of fucose of 60 % or less of the total amount of oligosaccharides (sugars) at Asn297, for the manufacture of a medicament for the treatment of cancer in combination with bendamustine.
  • the afucosylated anti-CD20 antibody binds CD20 with an KD of 10 ⁇ 9 M to 10 "13 mol/l.
  • the amount of fucose is between 40 % and 60 % of the total amount of oligosaccharides (sugars) at Asn297.
  • antibody encompasses the various forms of antibodies including but not being limited to whole antibodies, human antibodies, humanized antibodies and genetically engineered antibodies like monoclonal antibodies, chimeric antibodies or recombinant antibodies as well as fragments of such antibodies as long as the characteristic properties according to the invention are retained.
  • the terms "monoclonal antibody” or “monoclonal antibody composition” as used herein refer to a preparation of antibody molecules of a single amino acid composition.
  • human monoclonal antibody refers to antibodies displaying a single binding specificity which have variable and constant regions derived from human germline immunoglobulin sequences.
  • the human monoclonal antibodies are produced by a hybridoma which includes a B cell obtained from a transgenic non-human animal, e.g. a transgenic mouse, having a genome comprising a human heavy chain transgene and a light human chain transgene fused to an immortalized cell.
  • chimeric antibody refers to a monoclonal antibody comprising a variable region, i.e., binding region, from one source or species and at least a portion of a constant region derived from a different source or species, usually prepared by recombinant DNA techniques. Chimeric antibodies comprising a murine variable region and a human constant region are especially preferred. Such murine/human chimeric antibodies are the product of expressed immunoglobulin genes comprising DNA segments encoding murine immunoglobulin variable regions and DNA segments encoding human immunoglobulin constant regions.
  • Other forms of "chimeric antibodies" encompassed by the present invention are those in which the class or subclass has been modified or changed from that of the original antibody.
  • Such “chimeric” antibodies are also referred to as "class- switched antibodies.”
  • Methods for producing chimeric antibodies involve conventional recombinant DNA and gene transfection techniques now well known in the art. See, e.g., Morrison, S. L., et al., Proc. Natl. Acad Sci. USA 81 (1984) 6851-6855; US 5,202,238 and US 5,204,244.
  • the term "humanized antibody” refers to antibodies in which the framework or "complementarity determining regions” (CDR) have been modified to comprise the CDR of an immunoglobulin of different specificity as compared to that of the parent immunoglobulin.
  • CDR complementarity determining regions
  • a murine CDR is grafted into the framework region of a human antibody to prepare the "humanized antibody.”
  • human antibody is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences.
  • Human antibodies are well-known in the state of the art (van Dijk, M.A., and van de Winkel, J.G., Curr. Opin. Pharmacol. 5 (2001) 368- 374). Based on such technology, human antibodies against a great variety of targets can be produced. Examples of human antibodies are for example described in Kellermann, S.A., et al., Curr Opin Biotechnol. 13 (2002) 593-597.
  • recombinant human antibody is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies isolated from a host cell such as a NSO or CHO cell or from an animal (e.g. a mouse) that is transgenic for human immunoglobulin genes or antibodies expressed using a recombinant expression vector transfected into a host cell.
  • recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences in a rearranged form.
  • the recombinant human antibodies according to the invention have been subjected to in vivo somatic hypermutation.
  • the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
  • binding refers to the binding of the antibody to an epitope of the tumor antigen in an in vitro assay, preferably in an plasmon resonance assay (BIAcore, GE-Healthcare Uppsala, Sweden) with purified wild-type antigen.
  • the affinity of the binding is defined by the terms ka (rate constant for the association of the antibody from the antibody/antigen complex), k D (dissociation constant), and K D (k ⁇ >/ka).
  • Binding or specifically binding means a binding affinity (K D ) of 10 '8 mol/1 or less, preferably 10 "9 M to 10 "13 mol/1.
  • an afucosylated antibody according to the invention is specifically binding to the tumor antigen with a binding affinity (K 0 ) of 10 '8 mol/1 or less, preferably 10 "9 M to lO "13 rnol/l.
  • nucleic acid molecule is intended to include DNA molecules and RNA molecules.
  • a nucleic acid molecule may be single-stranded or double-stranded, but preferably is double-stranded DNA.
  • the "constant domains" are not involved directly in binding the antibody to an antigen but are involved in the effector functions (ADCC, complement binding, and CDC).
  • variable region denotes each of the pair of light and heavy chains which is involved directly in binding the antibody to the antigen.
  • the domains of variable human light and heavy chains have the same general structure and each domain comprises four framework (FR) regions whose sequences are widely conserved, connected by three "hypervariable regions” (or complementarity determining regions, CDRs).
  • the framework regions adopt a b-sheet conformation and the CDRs may form loops connecting the b-sheet structure.
  • the CDRs in each chain are held in their three-dimensional structure by the framework regions and form together with the CDRs from the other chain the antigen binding site.
  • hypervariable region or "antigen-binding portion of an antibody” when used herein refer to the amino acid residues of an antibody which are responsible for antigen-binding.
  • the hypervariable region comprises amino acid residues from the "complementarity determining regions” or "CDRs".
  • “Framework” or "FR” regions are those variable domain regions other than the hypervariable region residues as herein defined. Therefore, the light and heavy chains of an antibody comprise from N- to C-terminus the domains FRl, CDRl, FR2, CDR2, FR3,
  • CDR3, and FR4 are the region which contributes most to antigen binding.
  • CDR and FR regions are determined according to the standard definition of Kabat, et al., Sequences of Proteins of Immunological
  • Bendamustine is 4-[5-[Bis(2-chloroethyl)amino]-l-methylbenzimidazol-2-yl]buta- noic acid. Trade names are Ribomustin and Treanda; bendamustine is also known as SDX- 105). Bendamustine is a nitrogen mustard used in the treatment of chronic lymphocytic leukemia (CLL) (Kath, R., et al., J. Cancer Res. Clin. Oncol. 127 (2001) 48-54) and non-Hodgkin's lymphoma (NHL). It belongs to the family of drugs called alkylating agents. It is also being studied for the treatment of sarcoma (Bagchi, S., Lancet Oncol. 8 (2007) 674).
  • the term "afucosylated antibody” refers to an antibody of IgGl or IgG3 isotype
  • Antibodies which are recombinantly expressed in non glycomodified CHO host cells usually are fucosylated at Asn297 in an amount of at least 85 %. It should be understood that the term an afucosylated antibody as used herein includes an antibody having no fucose in its glycosylation pattern. It is commonly known that typical glycosylated residue position in an antibody is the asparagine at position 297 according to the EU numbering system (“Asn297").
  • EU numbering system or "EU index” is generally used when referring to a residue in an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991) expressly incorporated herein by reference).
  • EU index reported in Kabat et al, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991) expressly incorporated herein by reference.
  • an afucosylated antibody according to the invention means an antibody of
  • IgGl or IgG3 isotype(preferably of IgGl isotype) wherein the amount of fucose is 60 % or less of the total amount of oligosaccharides (sugars) at Asn297 (which means that at least 40 % or more of the oligosaccharides of the Fc region at Asn297 are afucosylated). In one embodiment the amount of fucose is between 40 % and 60 % of the oligosaccharides of the Fc region at Asn297.
  • the amount of fucose is 50 % or less, and in still another embodiment the amount of fucose is 30 % or less of the oligosaccharides of the Fc region at Asn297. In an alternative embodiment, the amount of fucose is 0% of the oligosaccharides of the Fc region at Asn297.
  • amount of fucose means the amount of said oligosaccharide (fucose) within the oligosaccharide (sugar) chain at Asn297, related to the sum of all oligosaccharides (sugars) attached to Asn 297 (e. g.
  • the oligosaccharides of the Fc region are bisected.
  • the afucosylated antibody according to the invention can be expressed in a glycomodified host cell engineered to express at least one nucleic acid encoding a polypeptide having GnTIII activity in an amount sufficient to partially fucosylate the oligosaccharides in the Fc region.
  • the polypeptide having GnTIII activity is a fusion polypeptide.
  • ot ⁇ ,6-fucosyltransferase activity of the host cell can be decreased or eliminated according to US 6,946,292 to generate glycomodified host cells.
  • the amount of antibody fucosylation can be predetermined e.g. either by fermentation conditions (e.g. fermentation time) or by combination of at least two antibodies with different fucosylation amount.
  • WO 2005/044859, WO 2004/065540, WO 2007/031875 Umana, P., et al., Nature Biotechnol. 17 (1999) 176-180, WO 99/154342, WO 2005/018572, WO 2006/116260, WO 2006/114700, WO 2005/011735, WO 2005/027966, WO 97/028267, US2006/0134709, US2005/0054048, US2005/0152894, WO 2003/035835, WO 2000/061739.
  • These glycoengineered antibodies have an increased ADCC.
  • Other glycoengineering methods yielding afucosylated antibodies according to the invention are described e.g.
  • one aspect of the invention is the use of an afucosylated anti-CD20 antibody of IgGl or IgG3 isotype (preferably of IgGl isotype) specifically binding to CD20 with an amount of fucose of 60 % or less of the total amount of oligosaccharides (sugars) at Asn297, for the manufacture of a medicament for the treatment of cancer in combination with bendamustine.
  • the amount of fucose is between 40 % and 60 % of the total amount of oligosaccharides (sugars) at Asn297.
  • CD20 also known as B-lymphocyte antigen CD20, B-lymphocyte surface antigen
  • the corresponding human gene is Membrane-spanning 4-domains, subfamily A, member 1, also known as MS4A1. This gene encodes a member of the membrane- spanning 4A gene family. Members of this nascent protein family are characterized by common structural features and similar intron/exon splice boundaries and display unique expression patterns among hematopoietic cells and nonlymphoid tissues.
  • This gene encodes the B-lymphocyte surface molecule which plays a role in the development and differentiation of B-cells into plasma cells.
  • This family member is localized to I lql2, among a cluster of family members.
  • Alternative splicing of this gene results in two transcript variants which encode the same protein.
  • CD20 and CD20 antigen are used interchangeably herein, and include any variants, isoforms and species homologs of human CD20 which are naturally expressed by cells or are expressed on cells transfected with the CD20 gene. Binding of an antibody of the invention to the CD20 antigen mediate the killing of cells expressing CD20 (e.g., a tumor cell) by inactivating CD20. The killing of the cells expressing CD20 may occur by one or more of the following mechanisms: Cell death/apoptosis induction, ADCC and CDC.
  • CD20 Synonyms of CD20, as recognized in the art, include B-lymphocyte antigen CD20, B-lymphocyte surface antigen Bl, Leu-16, Bp35, BM5, and LF5.
  • anti-CD20 antibody is an antibody that binds specifically to CD20 antigen.
  • two types of anti-CD20 antibodies can be distinguished according to Cragg, M.S., et al., Blood 103 (2004) 2738-2743; and Cragg, M.S., et al., Blood 101 (2003) 1045-1051, see Table 2.
  • Table 2 Properties of type I and type II anti-CD20 antibodies
  • type II anti-CD20 antibodies include e.g. humanized B-LyI antibody IgGl (a chimeric humanized IgGl antibody as disclosed in WO 2005/044859), 11B8 IgGl (as disclosed in WO 2004/035607), and AT80 IgGl.
  • type II anti-CD20 antibodies of the IgGl isotype show characteristic CDC properties.
  • Type II anti-CD20 antibodies have a decreased CDC (if IgGl isotype) compared to type I antibodies of the IgGl isotype.
  • type I anti-CD20 antibodies include e.g. rituximab, HI47 IgG3 (ECACC, hybridoma), 2C6 IgGl (as disclosed in WO 2005/103081), 2F2 IgGl (as disclosed and WO 2004/035607 and WO 2005/103081) and 2H7 IgGl (as disclosed in WO 2004/056312).
  • rituximab HI47 IgG3 (ECACC, hybridoma)
  • 2C6 IgGl as disclosed in WO 2005/103081
  • 2F2 IgGl as disclosed and WO 2004/035607 and WO 2005/103081
  • 2H7 IgGl as disclosed in WO 2004/056312
  • the afucosylated anti-CD20 antibodies according to the invention is in one embodiment a type II anti-CD20 antibody, in a more specific embodiment, the type II anti-CD20 antibody is an afucosylated humanized B-LyI antibody.
  • the afucosylated anti-CD20 antibodies according to the invention have an increased antibody dependent cellular cytotoxicity (ADCC) unlike anti-CD20 antibodies having no reduced fucose.
  • ADCC antibody dependent cellular cytotoxicity
  • ADCC antibody dependent cellular cytotoxicity
  • the assay uses target cells that are known to express the target antigen recognized by the antigen-binding region of the antibody; 2) the assay uses human peripheral blood mononuclear cells (PBMCs), isolated from blood of a randomly chosen healthy donor, as effector cells;
  • PBMCs peripheral blood mononuclear cells
  • the assay is carried out according to following protocol: i) the PBMCs are isolated using standard density centrifugation procedures and are suspended at 5 x 10 6 cells/ml in RPMI cell culture medium; ii) the target cells are grown by standard tissue culture methods, harvested from the exponential growth phase with a viability higher than 90 %, washed in RPMI cell culture medium, labeled with 100 micro-Curies of 51 Cr, washed twice with cell culture medium, and resuspended in cell culture medium at a density of 10 5 cells/ml; iii) 100 microliters of the final target cell suspension above are transferred to each well of a 96-well microtiter plate; iv) the antibody is serially-diluted from 4000 ng/ml to 0.04 ng/ml in cell culture medium and 50 microliters of the resulting antibody solutions are added to the target cells in the 96-well microtiter plate, testing in triplicate various antibody concentrations covering the whole concentration range above; v) for the maximum
  • "increased ADCC” is defined as either an increase in the maximum percentage of specific lysis observed within the antibody concentration range tested above, and/or a reduction in the concentration of antibody required to achieve one half of the maximum percentage of specific lysis observed within the antibody concentration range tested above.
  • the increase in ADCC is relative to the ADCC, measured with the above assay, mediated by the same antibody, produced by the same type of host cells, using the same standard production, purification, formulation and storage methods, which are known to those skilled in the art, but that has not been produced by host cells engineered to overexpress GnTIII.
  • ADCC increased ADCC
  • CDC complement-dependent cytotoxicity
  • CDC is found if the antibody induces at a concentration of 100 nM the lysis (cell death) of 20 % or more of the tumor cells after 4 hours.
  • the assay is performed preferably with 51 Cr or Eu labeled tumor cells and measurement of released 51 Cr or Eu. Controls include the incubation of the tumor target cells with complement but without the antibody.
  • the "rituximab” antibody reference antibody; example of a type I anti-CD20 antibody
  • This chimeric antibody contains human gamma 1 constant domains and is identified by the name "C2B8" in US 5,736,137 (Andersen et.
  • Rituximab is approved for the treatment of patients with relapsed or refracting low-grade or follicular, CD20 positive, B cell non-Hodgkin's lymphoma.
  • CDC human complement— dependent cytotoxicity
  • ADCC antibody-dependent cellular cytotoxicity
  • humanized B-LyI antibody refers to humanized B-LyI antibody as disclosed in WO 2005/044859 and WO 2007/031875, which were obtained from the murine monoclonal anti-CD20 antibody B-LyI (variable region of the murine heavy chain (VH): SEQ ID NO: 1 ; variable region of the murine light chain (VL): SEQ ID NO: 2- see Poppema, S. and Visser, L., Biotest Bulletin 3 (1987) 131-139) by chimerization with a human constant domain from IgGl and following humanization (see WO 2005/044859 and WO 2007/031875).
  • VH murine heavy chain
  • VL variable region of the murine light chain
  • the "humanized B-LyI antibody” has variable region of the heavy chain (VH) selected from group of SEQ ID NO:3 to SEQ ID NO:20 (B-HH2 to B-HH9 and B-HL8 to B-HLl 7 of WO 2005/044859 and WO 2007/031875). Especially preferred are Seq. ID No. 3, 4, 7, 9, 1 1, 13 and 15 (B-HH2, B-HH3, B- HH6, B-HH8, B-HL8, B-HLI l and B-HLl 3 of WO 2005/044859 and WO 2007/031875). In one specific embodiment, the "humanized B-LyI antibody” has variable region of the light chain (VL) of SEQ ID No.
  • the "humanized B-LyI antibody” has a variable region of the heavy chain (VH) of SEQ ID NO:7 (B-HH6 of WO 2005/044859 and WO 2007/031875) and a variable region of the light chain (VL) of SEQ ID No. 20 (B-KVl of WO 2005/044859 and WO 2007/031875).
  • the humanized B-LyI antibody is an IgGl antibody.
  • such afucosylated humanized B-LyI antibodies are glycoengineered (GE) in the Fc region according to the procedures described in WO 2005/044859, WO 2004/065540, WO 2007/031875, Umana, P., et al., Nature Biotechnol. 17 (1999) 176-180 and WO 99/154342.
  • the anti-CD20 antibody used is afucosylated glyco-engineered humanized B-LyI known as B-HH6-B-KV1 GE.
  • Such glycoengineered humanized B-LyI antibodies have an altered pattern of glycosylation in the Fc region, preferably having a reduced level of fucose residues.
  • the amount of fucose is 60 % or less of the total amount of oligosaccharides at Asn297 (in one embodiment the amount of fucose is between
  • the amount of fucose is 50 % or less, and in still another embodiment the amount of fucose is 30 % or less, and in yet another embodiment, the amount of fucose is 0%).
  • the oligosaccharides of the Fc region are bisected. These glycoengineered humanized B-LyI antibodies have an increased ADCC.
  • the oligosaccharide component can significantly affect properties relevant to the efficacy of a therapeutic glycoprotein, including physical stability, resistance to protease attack, interactions with the immune system, pharmacokinetics, and specific biological activity. Such properties may depend not only on the presence or absence, but also on the specific structures, of oligosaccharides. Some generalizations between oligosaccharide structure and glycoprotein function can be made. For example, certain oligosaccharide structures mediate rapid clearance of the glycoprotein from the bloodstream through interactions with specific carbohydrate binding proteins, while others can be bound by antibodies and trigger undesired immune reactions. (Jenkins, N., et al., Nature Biotechnol. 14 (1996) 975-
  • Mammalian cells are the excellent hosts for production of therapeutic glycoproteins, due to their capability to glycosylate proteins in the most compatible form for human application. (Cumming, D. A., et al., Glycobiology 1 (1991) 115- 30; Jenkins, N., et al., Nature Biotechnol. 14 (1996) 975-981). Bacteria very rarely glycosylate proteins, and like other types of common hosts, such as yeasts, filamentous fungi, insect and plant cells, yield glycosylation patterns associated with rapid clearance from the blood stream, undesirable immune interactions, and in some specific cases, reduced biological activity. Among mammalian cells, Chinese hamster ovary (CHO) cells have been most commonly used during the last two decades.
  • these cells allow consistent generation of genetically stable, highly productive clonal cell lines. They can be cultured to high densities in simple bioreactors using serum free media, and permit the development of safe and reproducible bioprocesses.
  • Other commonly used animal cells include baby hamster kidney (BHK) cells, NSO- and SP2/0- mouse myeloma cells. More recently, production from transgenic animals has also been tested. (Jenkins, N., et al., Nature Biotechnol. 14 (1996) 975-981).
  • All antibodies contain carbohydrate structures at conserved positions in the heavy chain constant regions, with each isotype possessing a distinct array of N-linked carbohydrate structures, which variably affect protein assembly, secretion or functional activity.
  • N-linked carbohydrate structures which variably affect protein assembly, secretion or functional activity.
  • the structure of the attached N-linked carbohydrate varies considerably, depending on the degree of processing, and can include high-mannose, multiply- branched as well as biantennary complex oligosaccharides. (Wright, A., and Morrison, S.L., Trends Biotech. 15 (1997) 26-32).
  • IgGl type antibodies the most commonly used antibodies in cancer immunotherapy, are glycoproteins that have a conserved N-linked glycosylation site at Asn297 in each CH2 domain.
  • the two complex biantennary oligosaccharides attached to Asn297 are buried between the CH2 domains, forming extensive contacts with the polypeptide backbone, and their presence is essential for the antibody to mediate effector functions such as antibody dependent cellular cytotoxicity (ADCC) (Lifely, M. R., et al., Glycobiology 5 (1995) 813-822; Jefferis, R., et al., Immunol. Rev.
  • ADCC antibody dependent cellular cytotoxicity
  • the antibody chCE7 belongs to a large class of unconjugated monoclonal antibodies which have high tumor affinity and specificity, but have too little potency to be clinically useful when produced in standard industrial cell lines lacking the GnTIII enzyme (Umana, P., et al., Nature Biotechnol. 17 (1999) 176-180).
  • cancer as used herein includes lymphomas, lymphocytic leukemias, lung cancer, non small cell lung (NSCL) cancer, bronchioloalviolar cell lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma
  • the term "expression of the CD20" antigen is intended to indicate an significant level of expression of the CD20 antigen in a cell, preferably on the cell surface of a
  • T- or B- cell more preferably a B-cell, from a tumor or cancer, respectively, preferably a non-solid tumor.
  • Patients having a "CD20 expressing cancer” can be determined by standard assays known in the art. For example, CD20 antigen expression can be measured using immunohistochemical (IHC) detection, FACS or via PCR-based detection of the corresponding mRNA.
  • IHC immunohistochemical
  • CD20 expressing cancer refers to all cancers in which the cancer cells show an expression of the CD20 antigen.
  • CD20 expressing cancer refers to lymphomas (preferably B-cell Non- Hodgkin's lymphomas (NHL)) and lymphocytic leukemias.
  • lymphomas and lymphocytic leukemias include e.g. a) follicular lymphomas, b) Small Non-
  • Cleaved Cell Lymphomas/ Burkitt's lymphoma including endemic Burkitt's lymphoma, sporadic Burkitt's lymphoma and Non-Burkitt's lymphoma
  • marginal zone lymphomas including extranodal marginal zone B cell lymphoma (Mucosa- associated lymphatic tissue lymphomas, MALT), nodal marginal zone B cell lymphoma and splenic marginal zone lymphoma
  • MALT extranodal marginal zone B cell lymphoma- associated lymphatic tissue lymphomas
  • MCL Large Cell Lymphoma (including B-cell diffuse large cell lymphoma (DLCL), Diffuse Mixed Cell Lymphoma, Immunoblastic Lymphoma, Primary Mediastinal B-CeIl Lymphoma, Angiocentric Lymphoma-Pulmonary B-CeIl Lymphoma) f) hairy cell leukemia, g ) lymphocytic lymphoma, Waldenstrom's macroglobulinemia, h) acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), B-cell prolymphocyte leukemia, i) plasma cell neoplasms, plasma cell myeloma, multiple myeloma, plasmacytoma j) Hodgkin's disease.
  • ALL acute lymphocytic leukemia
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • the CD20 expressing cancer is a B-cell Non-Hodgkin's lymphomas (NHL). In another embodiment, the CD20 expressing cancer is a
  • Mantle cell lymphoma MCL
  • ALL acute lymphocytic leukemia
  • CLL chronic lymphocytic leukemia
  • DLCL B-cell diffuse large cell lymphoma
  • Burkitt's lymphoma hairy cell leukemia
  • follicular lymphoma multiple myeloma
  • marginal zone lymphoma marginal zone lymphoma
  • PTLD post transplant lymphoproliferative disorder
  • HIV associated lymphoma Waldenstrom's macroglobulinemia, or primary CNS lymphoma.
  • a method of treating when applied to, for example, cancer refers to a procedure or course of action that is designed to reduce or eliminate the number of cancer cells in a patient, or to alleviate the symptoms of a cancer.
  • a method of treating does not necessarily mean that the cancer cells or other disorder will, in fact, be eliminated, that the number of cells or disorder will, in fact, be reduced, or that the symptoms of a cancer or other disorder will, in fact, be alleviated.
  • a method of treating cancer will be performed even with a low likelihood of success, but which, given the medical history and estimated survival expectancy of a patient, is nevertheless deemed to induce an overall beneficial course of action.
  • co-administration refers to the administration of said afucosylated anti-CD20, and bendamustine as one single formulation or as two separate formulations.
  • the co-administration can be simultaneous or sequential in either order, wherein preferably there is a time period while both (or all) active agents simultaneously exert their biological activities.
  • Said anti-CD20 afucosylated antibody and bendamustine are co-administered either simultaneously or sequentially (e.g. via an intravenous (i.v.) through a continuous infusion (one for the anti-CD20 antibody and eventually one for bendamustine).
  • both therapeutic agents are co-administered sequentially the dose is administered either on the same day in two separate administrations, or one of the agents is administered on day 1 and the second is co-administered on day 2 to day 7, preferably on day 2 to 4.
  • the term “sequentially” means within 7 days after the dose of the first component (bendamustine or antibody), preferably within 4 days after the dose of the first component; and the term “simultaneously” means at the same time.
  • co-administration with respect to the maintenance doses of said afucosylated anti-CD20 antibody and bendamustine mean that the maintenance doses can be either co-administered simultaneously, if the treatment cycle is appropriate for both drugs, e.g.
  • bendamustine is e.g. administered e.g. every first to third day and said afucosylated antibody is administered every week.
  • the maintenance doses are co-administered sequentially, either within one or within several days.
  • the antibodies are administered to the patient in a "therapeutically effective amount” (or simply “effective amount") which is the amount of the respective compound or combination that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • a “therapeutically effective amount” or simply “effective amount” which is the amount of the respective compound or combination that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the amount of co-administration of said anti-CD20 afucosylated antibody and bendamustine and the timing of co-administration will depend on the type (species, gender, age, weight, etc.) and condition of the patient being treated and the severity of the disease or condition being treated.
  • Said afucosylated anti-CD20 antibody and bendamustine are suitably co-administered to the patient at one time or over a series of treatments. If the administration is intravenous the initial infusion time for said afucosylated anti-CD20 antibody or bendamustine may be longer than subsequent infusion times, for instance approximately 90 minutes for the initial infusion, and approximately 30 minutes for subsequent infusions (if the initial infusion is well tolerated). Depending on the type and severity of the disease, about 1 ⁇ g /kg to 50 mg/kg (e.g.
  • afucosylated anti-CD20 antibody preferably the afucosylated humanized B-LyI antibody
  • the preferred dosage of said afucosylated anti-CD20 antibody will be in the range from about 0.05mg/kg to about 30mg/kg.
  • one or more doses of about 0.5mg/kg, 2.0mg/kg, 4.0mg/kg, lOmg/kg or 30mg/kg (or any combination thereof) may be co-administered to the patient.
  • the dosage of bendamustine will be in the range from 0.01 mg/kg to about 30 mg/kg, e.g. 0.1 mg/kg to lO.Omg/kg.
  • the dosage and the administration schedule of said afucosylated antibody and bedamustine can differ, e.g., the said afucosylated anti-CD20 antibody may be administered e.g. every one to three weeks and bendamustine may be administered daily or every 2 to 10 days. An initial higher loading dose, followed by one or more lower doses may also be administered.
  • the preferred dosage of said afucosylated anti-CD20 antibody (preferably the afucosylated humanized B-LyI antibody) will be 800 to 1200 mg on day 1 , 8, 15 of a 6- week-dosage-cycle and then in a dosage of 800 to 1200 mg on day 1 of up to five 4- week-dosage-cycles and the preferred dosage of bendamustine will be, e.g, 80 mg/m2 to 110 mg/ m2 (in one embodiment 1 10 mg/ m2, in another embodiment 90 mg/m2) on day 1 and 2 (infused intravenously over 30 minutes on days 1 and 2) of up to six 4-week-dosage-cycles.
  • the dosage of said afucosylated anti-CD20 antibody can be 800 to 1200 mg (e.g., 1000 mg) on day 1 up to eight 3 -week-dosage-cycles.
  • the medicament is useful for preventing or reducing metastasis or further dissemination in such a patient suffering from cancer, preferably CD20 expressing cancer.
  • the medicament is useful for increasing the duration of survival of such a patient, increasing the progression free survival of such a patient, increasing the duration of response, resulting in a statistically significant and clinically meaningful improvement of the treated patient as measured by the duration of survival, progression free survival, response rate or duration of response.
  • the medicament is useful for increasing the response rate in a group of patients.
  • additional other cytotoxic, chemotherapeutic or anti-cancer agents, or compounds that enhance the effects of such agents e.g.
  • cytokines may be used in the afucosylated anti-CD20 antibody and bendamustine combination treatment of cancer.
  • Such molecules are suitably present in combination in amounts that are effective for the purpose intended.
  • the said afucosylated anti-CD20 antibody and bendamustine combination treatment is used without such additional cytotoxic, chemotherapeutic or anti-cancer agents, or compounds that enhance the effects of such agents.
  • Such agents include, for example: alkylating agents or agents with an alkylating action, such as cyclophosphamide (CTX; e.g. Cytoxan®), chlorambucil (CHL; e.g. leukeran®), cisplatin (CisP; e.g. platinol®) busulfan (e.g. myleran®), melphalan, carmustine (BCNU), streptozotocin, triethylenemelamine (TEM), mitomycin C, and the like; anti-metabolites, such as methotrexate (MTX), etoposide (VP 16; e.g.
  • vepesid® 6-mercaptopurine (6MP), 6-thiocguanine (6TG), cytarabine (Ara-C), 5-fluorouracil (5-FU), capecitabine (e.g. Xeloda®), dacarbazine (DTIC), and the like; antibiotics, such as actinomycin D, doxorubicin (DXR; e.g.
  • adriamycin® daunorubicin (daunomycin), bleomycin, mithramycin and the like
  • alkaloids such as vinca alkaloids such as vincristine (VCR), vinblastine, and the like
  • antitumor agents such as paclitaxel (e.g. taxol®) and paclitaxel derivatives, the cytostatic agents, glucocorticoids such as dexamethasone (DEX; e.g.
  • decadron® and corticosteroids such as prednisone, nucleoside enzyme inhibitors such as hydroxyurea, amino acid depleting enzymes such as asparaginase, leucovorin and other folic acid derivatives, and similar, diverse antitumor agents.
  • the following agents may also be used as additional agents: arnifostine (e.g. ethyol®), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, lomustine (CCNU), doxorubicin lipo (e.g. doxil®), gemcitabine (e.g. gemzar®), daunorubicin lipo (e.g.
  • daunoxome® procarbazine, mitomycin, docetaxel (e.g. taxotere®), aldesleukin, carboplatin, oxaliplatin, cladribine, camptothecin, CPT 11 (irinotecan), 10-hydroxy 7-ethyl-camptothecin (SN38), floxuridine, fludarabine, ifosfamide, idarubicin, mesna, interferon beta, interferon alpha, mitoxantrone, topotecan, leuprolide, megestrol, melphalan, mercaptopurine, plicamycin, mitotane, pegaspargase, pentostatin, pipobroman, plicamycin, tamoxifen, teniposide, testolactone, thioguanine, thiotepa, uracil mustard, vinorelbine, chlorambucil.
  • the afucosy
  • cytotoxic and anticancer agents described above as well as antiproliferative target-specific anticancer drugs like protein kinase inhibitors in chemotherapeutic regimens is generally well characterized in the cancer therapy arts, and their use herein falls under the same considerations for monitoring tolerance and effectiveness and for controlling administration routes and dosages, with some adjustments.
  • the actual dosages of the cytotoxic agents may vary depending upon the patient's cultured cell response determined by using histoculture methods. Generally, the dosage will be reduced compared to the amount used in the absence of additional other agents. Typical dosages of an effective cytotoxic agent can be in the ranges recommended by the manufacturer, and where indicated by in vitro responses or responses in animal models, can be reduced by up to about one order of magnitude concentration or amount.
  • the actual dosage will depend upon the judgment of the physician, the condition of the patient, and the effectiveness of the therapeutic method based on the in vitro responsiveness of the primary cultured malignant cells or histocultured tissue sample, or the responses observed in the appropriate animal models.
  • an effective amount of ionizing radiation may be carried out and/or a radiopharmaceutical may be used in addition to the afucosylated anti-CD20 antibody and bendamustine combination treatment of CD20 expressing cancer.
  • the source of radiation can be either external or internal to the patient being treated. When the source is external to the patient, the therapy is known as external beam radiation therapy (EBRT). When the source of radiation is internal to the patient, the treatment is called brachytherapy (BT).
  • Radioactive atoms for use in the context of this invention can be selected from the group including, but not limited to, radium, cesium- 137, indium- 192, americium-241, gold-198, cobalt-57, copper-67, technetium-99, iodine-123, iodine-131, and indium-I l l.
  • the afucosylated anti-CD20 antibody and bendamustine combination treatment is used without such ionizing radiation.
  • Radiation therapy is a standard treatment for controlling unresectable or inoperable tumors and/or tumor metastases. Improved results have been seen when radiation therapy has been combined with chemotherapy. Radiation therapy is based on the principle that high-dose radiation delivered to a target area will result in the death of reproductive cells in both tumor and normal tissues.
  • the radiation dosage regimen is generally defined in terms of radiation absorbed dose (Gy), time and fractionation, and must be carefully defined by the oncologist.
  • the amount of radiation a patient receives will depend on various considerations, but the two most important are the location of the tumor in relation to other critical structures or organs of the body, and the extent to which the tumor has spread.
  • a typical course of treatment for a patient undergoing radiation therapy will be a treatment schedule over a 1 to 6 week period, with a total dose of between 10 and 80 Gy administered to the patient in a single daily fraction of about 1.8 to 2.0 Gy, 5 days a week.
  • a preferred embodiment of this invention there is synergy when tumors in human patients are treated with the combination treatment of the invention and radiation.
  • afucosylated anti-CD20 antibodies can be administered to a patient according to known methods, such as by intravenous administration as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerobrospinal, subcutaneous, intra-articular, intrasynovial, or intrathecal routes. In one embodiment, such antibodies are administered by intravenous or subcutaneous administration. Bendamustine can be administered to a patient according to known methods, e.g.
  • intravenous administration as a bolus or by continuous infusion over a period of time
  • intramuscular, intraperitoneal, intracerobrospinal, subcutaneous, intraarticular, intrasynovial, intrathecal, or peroral routes is administered by intravenous or intraperitoneal administration.
  • a "pharmaceutically acceptable carrier” is intended to include any and all material compatible with pharmaceutical administration including solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other materials and compounds compatible with pharmaceutical administration. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • compositions can be obtained by processing the anti-CD20 antibody and/or bendamustine according to this invention with pharmaceutically acceptable, inorganic or organic carriers.
  • Lactose, corn starch or derivatives thereof, talc, stearic acids or it's salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules.
  • Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules.
  • Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like.
  • Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
  • compositions can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • a composition comprises both said afucosylated anti-CD20 antibody with an amount of fucose is 60 % or less (in one embodiment, said antibody is afiicosylated humanized B-LyI antibody) and bendamustine for use in the treatment of cancer, in particular, CD20 expressing cancer.
  • Said pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers.
  • the present invention further provides a pharmaceutical composition, in particular for use in cancer, comprising (i) an effective first amount of an afucosylated anti- CD20 antibody with an amount of fucose is 60 % or less (in one embodiment, an afucosylated humanized B-LyI antibody) , and (ii) an effective second amount of bendamustine.
  • Such composition optionally comprises pharmaceutically acceptable carriers and / or excipients.
  • compositions of the afucosylated anti-CD20 antibody alone used in accordance with the present invention are prepared for storage by mixing an antibody having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. (ed.) (1980)), in the form of lyophilized formulations or aqueous solutions.
  • Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine,
  • compositions of bendamustine can be similar to those describe above for the afucosylated anti-CD20 antibody.
  • afucosylated anti-CD20 antibody and bendamustine are formulated in two separate formulations..
  • the active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interracial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano- particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano- particles and nanocapsules
  • Sustained-release preparations may be prepared.
  • sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g. films, or microcapsules.
  • sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (US 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOTTM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.
  • the formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration
  • the present invention further provides a method for the treatment of cancer, comprising administering to a patient in need of such treatment (i) an effective first amount of an afucosylated anti-CD20 antibody with an amount of fucose is 60 % or less, (in one embodiment, an afucosylated humanized B-LyI antibody); and (ii) an effective second amount of bendamustine.
  • the amount of fucose of is between 40 % and 60 %.
  • said cancer is a CD20 expressing cancer.
  • said CD20 expressing cancer is a B-CeIl Non-Hodgkin's lymphoma (NHL).
  • NDL B-CeIl Non-Hodgkin's lymphoma
  • said afucosylated anti-CD20 antibody is a type II anti-CD20 antibody.
  • said antibody is a humanized B-LyI antibody.
  • said humanized B-LyI antibody is administered in a dosage of 800 to 1200 mg on day 1, 8, 15 of a 6- week-dosage-cycle and then in a dosage of 800 to 1200 mg on day 1 of up to five 4-week-dosage-cycles, and bendamustine is administered in a dosage of 80 mg/m2 to 1 10 mg/ m2 on day 1 and 2 of up to six 4- week-dosage-cycles.
  • the term "patient” preferably refers to a human in need of treatment with an afucosylated anti-CD20 antibody (e.g. a patient suffering from CD20 expressing cancer) for any purpose, and more preferably a human in need of such a treatment to treat cancer, or a precancerous condition or lesion.
  • an afucosylated anti-CD20 antibody e.g. a patient suffering from CD20 expressing cancer
  • a human in need of such a treatment to treat cancer, or a precancerous condition or lesion e.g. a patient suffering from CD20 expressing cancer
  • patient can also refer to non-human animals, preferably mammals such as dogs, cats, horses, cows, pigs, sheep and non-human primates, among others.
  • the invention further comprises an afucosylated anti-CD20 antibody, for the treatment of cancer in combination with bendamustine.
  • the invention further comprises an afucosylated anti-CD20 antibody with an amount of fucose is 60 % or less, and bendamustine for use in the treatment of cancer.
  • said afucosylated anti-CD20 antibody is a humanized B-LyI antibody.
  • the cancer is a CD20 expressing cancer , more preferably a B-CeIl Non- Hodgkin's lymphoma (NHL).
  • NDL B-CeIl Non- Hodgkin's lymphoma
  • said humanized B-LyI antibody is administered in a dosage of 800 to 1200 mg on day 1, 8, 15 of a 6-week-dosage-cycle and then in a dosage of 800 to 1200 mg on day 1 of up to five 4-week-dosage-cycles, and bendamustine is administered in a dosage of 80mg/m2 to 110 mg/ m2 on day 1 and 2 of up to six 4- week-dosage-cycles.
  • VL murine monoclonal anti-CD20 antibody B-LyI .
  • LyI glycoengineered B-HH6-B-KV1, see WO 2005/044859 and WO 2007/031875) was provided as stock solution (9.4 mg/ml) from GlycArt, Schlieren, Switzerland.
  • Antibody buffer included histidine, trehalose and polysorbate 20. Antibody solution was diluted appropriately in PBS from stock for prior injections.
  • the human Zl 38 mantle cell lymphoma cell line was routinely cultured in DMEM supplemented with 10 % fetal bovine serum (PAA Laboratories, Austria) and 2 mM L-glutamine at 37 °C in a water-saturated atmosphere at 8 % CO2. Passage 4 was used for transplantation. Cells were co-injected with Matrigel.
  • mice Female SCID beige mice; age 3—4 weeks at arrival (purchased from Charles River,
  • TGI tumor growth inhibition

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RU2012109445/15A RU2575820C2 (ru) 2009-08-14 2010-08-12 Комбинированная терапия нефукозилированным анти-cd20 антителом с бендамустином
RS20170647A RS56146B1 (sr) 2009-08-14 2010-08-12 Kombinovana terapija afukozilovanim cd20 antitelom i bendamustinom
MX2014015198A MX355849B (es) 2009-08-14 2010-08-12 Terapia de combinacion de un anticuerpo cd20 afucosilado y bendamustina.
LTEP10747168.2T LT2464382T (lt) 2009-08-14 2010-08-12 Gydymas afukozintu anti-cd20 antikūnu kartu su bendamustinu
SG2012008843A SG178324A1 (en) 2009-08-14 2010-08-12 Combination therapy of an afucosylated cd20 antibody with bendamustine
DK10747168.2T DK2464382T3 (en) 2009-08-14 2010-08-12 COMBINATION THERAPY OF AN AFUCOSYLATED CD20 ANTIBODY AND BENDAMUSTIN
EP10747168.2A EP2464382B1 (en) 2009-08-14 2010-08-12 Combination therapy of an afucosylated cd20 antibody with bendamustine
BR112012002855A BR112012002855A2 (pt) 2009-08-14 2010-08-12 "uso de um anticorpo anti-cd20 afucosilado e composição"
NZ597666A NZ597666A (en) 2009-08-14 2010-08-12 Combination therapy of an afucosylated cd20 antibody with bendamustine
MA34585A MA33469B1 (fr) 2009-08-14 2010-08-12 Polythérapie à base d'un anticorps afucosylé anti-cd20 et de bendamustine
JP2012524146A JP5646626B2 (ja) 2009-08-14 2010-08-12 ベンダムスチンとのアフコシル化ｃｄ２０抗体の併用療法
KR1020127006528A KR101425736B1 (ko) 2009-08-14 2010-08-12 벤다무스틴과 어푸코실화된 ｃｄ20 항체의 복합 요법
CA2769674A CA2769674C (en) 2009-08-14 2010-08-12 Combination therapy of an afucosylated cd20 antibody with bendamustine
CN201080035971XA CN102596245A (zh) 2009-08-14 2010-08-12 无岩藻糖基化cd20抗体与苯达莫司汀的联合疗法
AU2010281866A AU2010281866B2 (en) 2009-08-14 2010-08-12 Combination therapy of an afucosylated CD20 antibody with bendamustine
SI201031491T SI2464382T1 (sl) 2009-08-14 2010-08-12 Kombinirana terapija afukoziliranega protitelesa CD20 z bendamustinom
ES10747168.2T ES2630158T3 (es) 2009-08-14 2010-08-12 Terapia combinada de un anticuerpo CD20 afucosilado con bendamustina
MX2012001782A MX2012001782A (es) 2009-08-14 2010-08-12 Terapia de combinacion de un anticuerpo cd20 afucosilado y bendamustina.
UAA201202678A UA110096C2 (uk) 2009-08-14 2010-12-08 Комбінована терапія нефукозильованим анти-cd20 антитілом з бендамустином
IL217753A IL217753A (en) 2009-08-14 2012-01-26 Use of a 20cd epocylated antibody to make a cancer treatment drug in combination with bandamostine
ZA2012/00830A ZA201200830B (en) 2009-08-14 2012-02-02 Combination therapy of an afucosylated cd20 antibody with bendamustine
HRP20170972TT HRP20170972T1 (hr) 2009-08-14 2017-06-27 Kombinacijska terapija afukoziliranog cd20-protutijela s bendamustinom
CY20171100706T CY1119251T1 (el) 2009-08-14 2017-07-03 Θεραπεια συνδυασμου ενος αφουκοζυλιωμενου αντισωματος cd20 με μπενδαμουστινη
LU00045C LUC00045I2 (ko) 2009-08-14 2017-10-26
NO2017054C NO2017054I1 (no) 2009-08-14 2017-10-26 Obinutuzumab i kombinasjon med Bendamustin
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LTPA2017035C LTPA2017035I1 (lt) 2009-08-14 2017-10-31 Gydymas afukozintu anti-CD20 antikūnu kartu su bendamustinu

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012175874A1 (fr) * 2011-06-22 2012-12-27 Lfb Biotechnologies Utilisation d'un anticorps anti-cd20 a haute adcc pour le traitement de la maladie de waldenstrom
FR2980110A1 (fr) * 2011-09-20 2013-03-22 Lfb Biotechnologies Combinaison d'anticorps anti-cd20 et de bendamustine
EP3257866A1 (en) * 2016-06-17 2017-12-20 Academisch Medisch Centrum Modified anti-tnf antibody and use thereof in the treatment of ibd
US9879013B2 (en) 2010-05-31 2018-01-30 Ono Pharmaceutical Co., Ltd. Purinone derivative
US9896453B2 (en) 2011-11-29 2018-02-20 Ono Pharmaceutical Co., Ltd. Purinone derivative hydrochloride
US10137129B2 (en) 2014-03-25 2018-11-27 Ono Pharmaceutical Co., Ltd. Prophylactic agent and/or therapeutic agent for diffuse large B-cell lymphoma
US10239879B2 (en) 2015-04-09 2019-03-26 Ono Pharmaceutical Co., Ltd. Process for producing purinone derivative
US10494432B2 (en) 2007-07-16 2019-12-03 Genentech, Inc. Anti-CD79B antibodies and immunoconjugates and methods of use
US10544218B2 (en) 2008-01-31 2020-01-28 Genentech, Inc. Anti-CD79B antibodies and immunoconjugates and methods of use
US10981987B2 (en) 2007-07-16 2021-04-20 Genentech, Inc. Humanized anti-CD79b antibodies and immunoconjugates and methods of use
US11000510B2 (en) 2014-09-23 2021-05-11 Genentech, Inc. Methods of using anti-CD79b immunoconjugates

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* Cited by examiner, † Cited by third party
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US20230041197A1 (en) 2018-06-20 2023-02-09 Progenity, Inc. Treatment of a disease of the gastrointestinal tract with an immunomodulator
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Citations (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3773919A (en) 1969-10-23 1973-11-20 Du Pont Polylactide-drug mixtures
US5202238A (en) 1987-10-27 1993-04-13 Oncogen Production of chimeric antibodies by homologous recombination
US5204244A (en) 1987-10-27 1993-04-20 Oncogen Production of chimeric antibodies by homologous recombination
WO1997028267A1 (en) 1996-02-02 1997-08-07 Repligen Corporation Antibodies and immunoglobulin fusion proteins having modified effector functions and uses therefor
US5736137A (en) 1992-11-13 1998-04-07 Idec Pharmaceuticals Corporation Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma
WO1999054342A1 (en) 1998-04-20 1999-10-28 Pablo Umana Glycosylation engineering of antibodies for improving antibody-dependent cellular cytotoxicity
WO1999060023A1 (en) 1998-05-15 1999-11-25 Imclone Systems Incorporated Treatment of human tumors with radiation and inhibitors of growth factor receptor tyrosine kinases
WO2000061739A1 (en) 1999-04-09 2000-10-19 Kyowa Hakko Kogyo Co., Ltd. Method for controlling the activity of immunologically functional molecule
WO2003035835A2 (en) 2001-10-25 2003-05-01 Genentech, Inc. Glycoprotein compositions
WO2003055993A1 (fr) 2001-12-25 2003-07-10 Kyowa Hakko Kogyo Co., Ltd. Composition d'un anticorps qui se lie spécifiquement à cd20
WO2004035607A2 (en) 2002-10-17 2004-04-29 Genmab A/S Human monoclonal antibodies against cd20
WO2004056312A2 (en) 2002-12-16 2004-07-08 Genentech, Inc. Immunoglobulin variants and uses thereof
WO2004065540A2 (en) 2003-01-22 2004-08-05 Glycart Biotechnology Ag Fusion constructs and use of same to produce antibodies with increased fc receptor binding affinity and effector function
WO2004103301A2 (en) * 2003-05-16 2004-12-02 Hybridon, Inc. Synergistic treatment of cancer using immunomers in conjunction with chemotherapeutic agents
WO2005011735A1 (en) 2003-07-29 2005-02-10 Morphotek, Inc. Antibodies and methods for generating genetically altered antibodies with enhanced effector function
WO2005018572A2 (en) 2003-08-22 2005-03-03 Biogen Idec Ma Inc. Improved antibodies having altered effector function and methods for making the same
WO2005027966A2 (en) 2003-09-05 2005-03-31 Genentech, Inc. Antibodies with altered effector functions
WO2005044859A2 (en) 2003-11-05 2005-05-19 Glycart Biotechnology Ag Cd20 antibodies with increased fc receptor binding affinity and effector function
US6946292B2 (en) 2000-10-06 2005-09-20 Kyowa Hakko Kogyo Co., Ltd. Cells producing antibody compositions with increased antibody dependent cytotoxic activity
WO2005103081A2 (en) 2004-04-20 2005-11-03 Genmab A/S Human monoclonal antibodies against cd20
US20050249722A1 (en) 2000-04-12 2005-11-10 Laboratoire Francais Du Fractionnement Et Des Biotechnologies Monoclonal antibodies with enhanced ADCC function
US20060134709A1 (en) 2004-11-10 2006-06-22 Jeffery Stavenhagen Engineering Fc antibody regions to confer effector function
WO2006116260A2 (en) 2005-04-26 2006-11-02 Medimmune, Inc. Modulation of antibody effector function by hinge domain engineering
WO2006114700A2 (en) 2005-04-26 2006-11-02 Bioren, Inc. Method of producing human igg antibodies with enhanced effector functions
WO2007031875A2 (en) 2005-08-26 2007-03-22 Glycart Biotechnology Ag Modified antigen binding molecules with altered cell signaling activity
WO2008077546A1 (en) 2006-12-22 2008-07-03 F. Hoffmann-La Roche Ag Antibodies against insulin-like growth factor i receptor and uses thereof
WO2009053038A2 (en) * 2007-10-24 2009-04-30 F. Hoffmann-La Roche Ag Combination therapy of a type ii anti-cd20 antibody with a proteasome inhibitor
WO2010083365A1 (en) * 2009-01-16 2010-07-22 Glaxosmithkline Llc Treatment of a cancer using a combination of bendamustine and an anti-cd20 antibody

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2642787T3 (es) * 2005-10-21 2017-11-20 Lfb Usa, Inc. Anticuerpos con actividad de citotoxicidad celular dependiente de anticuerpos mejorada, métodos para su producción y uso
WO2009083009A2 (en) * 2008-01-03 2009-07-09 Genmab A/S Monoclonal antibodies against cd32b
EP2419470B1 (en) * 2009-04-15 2016-03-30 Invista Technologies S.à.r.l. Improving miscibility of otherwise immiscible compounds

Patent Citations (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3773919A (en) 1969-10-23 1973-11-20 Du Pont Polylactide-drug mixtures
US5202238A (en) 1987-10-27 1993-04-13 Oncogen Production of chimeric antibodies by homologous recombination
US5204244A (en) 1987-10-27 1993-04-20 Oncogen Production of chimeric antibodies by homologous recombination
US5736137A (en) 1992-11-13 1998-04-07 Idec Pharmaceuticals Corporation Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma
WO1997028267A1 (en) 1996-02-02 1997-08-07 Repligen Corporation Antibodies and immunoglobulin fusion proteins having modified effector functions and uses therefor
US6602684B1 (en) 1998-04-20 2003-08-05 Glycart Biotechnology Ag Glycosylation engineering of antibodies for improving antibody-dependent cellular cytotoxicity
WO1999054342A1 (en) 1998-04-20 1999-10-28 Pablo Umana Glycosylation engineering of antibodies for improving antibody-dependent cellular cytotoxicity
WO1999060023A1 (en) 1998-05-15 1999-11-25 Imclone Systems Incorporated Treatment of human tumors with radiation and inhibitors of growth factor receptor tyrosine kinases
WO2000061739A1 (en) 1999-04-09 2000-10-19 Kyowa Hakko Kogyo Co., Ltd. Method for controlling the activity of immunologically functional molecule
US20050249722A1 (en) 2000-04-12 2005-11-10 Laboratoire Francais Du Fractionnement Et Des Biotechnologies Monoclonal antibodies with enhanced ADCC function
US6946292B2 (en) 2000-10-06 2005-09-20 Kyowa Hakko Kogyo Co., Ltd. Cells producing antibody compositions with increased antibody dependent cytotoxic activity
WO2003035835A2 (en) 2001-10-25 2003-05-01 Genentech, Inc. Glycoprotein compositions
WO2003055993A1 (fr) 2001-12-25 2003-07-10 Kyowa Hakko Kogyo Co., Ltd. Composition d'un anticorps qui se lie spécifiquement à cd20
WO2004035607A2 (en) 2002-10-17 2004-04-29 Genmab A/S Human monoclonal antibodies against cd20
WO2004056312A2 (en) 2002-12-16 2004-07-08 Genentech, Inc. Immunoglobulin variants and uses thereof
WO2004065540A2 (en) 2003-01-22 2004-08-05 Glycart Biotechnology Ag Fusion constructs and use of same to produce antibodies with increased fc receptor binding affinity and effector function
WO2004103301A2 (en) * 2003-05-16 2004-12-02 Hybridon, Inc. Synergistic treatment of cancer using immunomers in conjunction with chemotherapeutic agents
WO2005011735A1 (en) 2003-07-29 2005-02-10 Morphotek, Inc. Antibodies and methods for generating genetically altered antibodies with enhanced effector function
US20050054048A1 (en) 2003-07-29 2005-03-10 Luigi Grasso Antibodies and methods for generating genetically altered antibodies with enhanced effector function
WO2005018572A2 (en) 2003-08-22 2005-03-03 Biogen Idec Ma Inc. Improved antibodies having altered effector function and methods for making the same
US20050152894A1 (en) 2003-09-05 2005-07-14 Genentech, Inc. Antibodies with altered effector functions
WO2005027966A2 (en) 2003-09-05 2005-03-31 Genentech, Inc. Antibodies with altered effector functions
WO2005044859A2 (en) 2003-11-05 2005-05-19 Glycart Biotechnology Ag Cd20 antibodies with increased fc receptor binding affinity and effector function
WO2005103081A2 (en) 2004-04-20 2005-11-03 Genmab A/S Human monoclonal antibodies against cd20
US20060134709A1 (en) 2004-11-10 2006-06-22 Jeffery Stavenhagen Engineering Fc antibody regions to confer effector function
WO2006116260A2 (en) 2005-04-26 2006-11-02 Medimmune, Inc. Modulation of antibody effector function by hinge domain engineering
WO2006114700A2 (en) 2005-04-26 2006-11-02 Bioren, Inc. Method of producing human igg antibodies with enhanced effector functions
WO2007031875A2 (en) 2005-08-26 2007-03-22 Glycart Biotechnology Ag Modified antigen binding molecules with altered cell signaling activity
WO2008077546A1 (en) 2006-12-22 2008-07-03 F. Hoffmann-La Roche Ag Antibodies against insulin-like growth factor i receptor and uses thereof
WO2009053038A2 (en) * 2007-10-24 2009-04-30 F. Hoffmann-La Roche Ag Combination therapy of a type ii anti-cd20 antibody with a proteasome inhibitor
WO2010083365A1 (en) * 2009-01-16 2010-07-22 Glaxosmithkline Llc Treatment of a cancer using a combination of bendamustine and an anti-cd20 antibody

Non-Patent Citations (61)

* Cited by examiner, † Cited by third party
Title
ANDERSON, K.C. ET AL., BLOOD, vol. 63, 1984, pages 1424 - 1433
BAGCHI, S., LANCET ONCOL., vol. 8, 2007, pages 674
BLOOD, vol. 102, no. 11, 16 November 2003 (2003-11-16), 45TH ANNUAL MEETING OF THE AMERICAN SOCIETY OF HEMATOLOGY; SAN DIEGO, CA, USA; DECEMBER 06-09, 2003, pages 104a, ISSN: 0006-4971 *
BLOOD, vol. 112, no. 11, November 2008 (2008-11-01), 50TH ANNUAL MEETING OF THE AMERICAN- SOCIETY-OF-HEMATOLOGY; SAN FRANCISCO, CA, USA; DECEMBER 06 -09, 2008, pages 128, ISSN: 0006-4971 *
BLOOD, vol. 112, no. 11, November 2008 (2008-11-01), 50TH ANNUAL MEETING OF THE AMERICAN- SOCIETY-OF-HEMATOLOGY; SAN FRANCISCO, CA, USA; DECEMBER 06 -09, 2008, pages 93, ISSN: 0006-4971 *
CHESON BRUCE D ET AL: "Bendamustine: rebirth of an old drug", JOURNAL OF CLINICAL ONCOLOGY, AMERICAN SOCIETY OF CLINICAL ONCOLOGY, US, vol. 27, no. 9, 20 March 2009 (2009-03-20), pages 1492 - 1501, XP009124323, ISSN: 0732-183X *
CHESON, B.D. ET AL., J CLIN ONCOL., vol. 27, no. 9, 2009, pages 1492 - 501
CRAGG, M.S. ET AL., BLOOD, vol. 101, 2003, pages 1045 - 1051
CRAGG, M.S. ET AL., BLOOD, vol. 103, 2004, pages 2738 - 2743
CUMMING, D.A. ET AL., GLYCOBIOLOGY, vol. 1, 1991, pages 115 - 30
DATABASE BIOSIS [online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; 16 November 2003 (2003-11-16), RUMMEL MATHIAS J ET AL: "Bendamustine and rituximab act synergistically in vitro and are effective in the treatment of relapsed or refractory indolent and mantle-cell lymphomas.", XP002559058, Database accession no. PREV200400172552 *
DATABASE BIOSIS [online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; November 2008 (2008-11-01), FISCHER KIRSTEN ET AL: "Bendamustine in Combination with Rituximab (BR) for Patients with Relapsed Chronic Lymphocytic Leukemia (CLL): A Multicentre Phase II Trial of the German CLL Study Group (GCLLSG)", XP002559057, Database accession no. PREV200900257032 *
DATABASE BIOSIS [online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; November 2008 (2008-11-01), SALLES GILLES ANDRE ET AL: "A Phase I/II Study of RO5072759 (GA101) in Patients with Relapsed/Refractory CD20(+) Malignant Disease", XP002559059, Database accession no. PREV200900256936 *
DAVIES, J. ET AL., BIOTECHNOL. BIOENG., vol. 74, 2001, pages 288 - 294
EINFELD, D.A. ET AL., EMBO J., vol. 7, 1988, pages 711 - 7
EINFELD, D.A. ET AL., EMBO J., vol. 7, 1988, pages 711 - 717
HOFFMANN-LA ROCHE: "A Study of RO5072759 With Chlorambucil in Patients With Previously Untreated Chronic Lymphocytic Leukemia", CLINICAL TRIALS, 6 November 2009 (2009-11-06), XP002559062, Retrieved from the Internet <URL:http://clinicaltrials.gov/ct2/show/NCT01010061?intr=ro5072759&rank=4> [retrieved on 20091204] *
JEFFERIS, R. ET AL., IMMUNOL. REV., vol. 163, 1998, pages 59 - 76
JENKINS, N. ET AL., NATURE BIOTECHNOL., vol. 14, 1996, pages 975 - 981
KANDA, Y. ET AL., BIOTECHNOL. BIOENG., vol. 94, 2004, pages 680 - 688
KATH, R. ET AL., J. CANCER RES. CLIN. ONCOL., vol. 127, 2001, pages 48 - 54
KELLERMANN, S.A. ET AL., CURR OPIN BIOTECHNOL., vol. 13, 2002, pages 593 - 597
KNAUF W: "Bendamustine in the treatment of chronic lymphocytic leukemia", EXPERT REVIEW OF ANTICANCER THERAPY 2009 EXPERT REVIEWS LTD. GBR, vol. 9, no. 2, 13 August 2009 (2009-08-13), pages 165 - 174, XP008115831, ISSN: 1473-7140 *
KNAUF, W., EXPERT REV ANTICANCER THER., vol. 9, no. 2, 2009, pages 165 - 74
LIDA, S. ET AL., CLIN. CANCER RES., vol. 12, 2006, pages 2879 - 2887
LIFELY, M.R. ET AL., GLYCOBIOLOGY, vol. 5, 1995, pages 813 - 822
LIFELY, M.R. ET AL., GLYCOBIOLOGY, vol. 5, no. 8, 1995, pages 813 - 22
MIMURA, Y. ET AL., J. BIOL. CHEM., vol. 276, 2001, pages 45539 - 45547
MORRISON, S.L. ET AL., PROC. NATL. ACAD SCI. USA, vol. 81, 1984, pages 6851 - 6855
NATSUME, A. ET AL., J. IMMUNOL. METHODS, vol. 306, 2005, pages 93 - 103
NEUBERGER, M.S. ET AL., NATURE, vol. 314, 1985, pages 268 - 270
NIWA, R. ET AL., J. IMMUNOL. METHODS, vol. 306, 2005, pages 151 - 160
PLOSKER GREG L ET AL: "Bendamustine A Review of its Use in the Management of Indolent Non-Hodgkin Lymphoma", DRUGS, ADIS INTERNATIONAL LTD, NZ, vol. 68, no. 18, 1 January 2008 (2008-01-01), pages 2645 - 2660, XP009121943, ISSN: 0012-6667 *
PLOSKER, G.L. ET AL., DRUGS., vol. 68, no. 18, 2008, pages 2645 - 60
POPPEMA, S.; VISSER, L., BIOTEST BULLETIN, vol. 3, 1987, pages 131 - 139
RADAEV, S. ET AL., J. BIOL. CHEM., vol. 276, 2001, pages 16478 - 16483
RAJU, T.S., BIOPROCESS INT., vol. 1, 2003, pages 44 - 53
REFF, M.E., BLOOD, vol. 83, no. 2, 1994, pages 435 - 445
RIECHMANN, L. ET AL., NATURE, vol. 332, 1988, pages 323 - 327
ROBAK T: "How to improve the treatment outcome in chronic lymphocytic leukemia?", LEUKEMIA RESEARCH, 13 August 2009 (2009-08-13), pages 1 - 4, XP002559060, DOI: 10.1016/j.leukres.2009.07.033 *
ROUTIER, F.H., GLYCOCONJUGATE J., vol. 14, 1997, pages 201 - 207
SATOH, M. ET AL., EXPERT OPIN. BIOL. THER., vol. 6, 2006, pages 1161 - 1173
SHIELDS, R.L. ET AL., J. BIOL. CHEM., vol. 276, 2001, pages 6591 - 6604
SHIELDS, R.L. ET AL., J. BIOL. CHEM., vol. 277, 2002, pages 26733 - 26740
SHINKAWA, T. ET AL., J BIOL CHEM, vol. 278, 2003, pages 3466 - 3473
SIMMONS, L.C. ET AL., J. IMMUNOL. METHODS, vol. 263, 2002, pages 133 - 147
STAMENKOVIC, I. ET AL., J. EXP. MED., vol. 167, 1988, pages 1975 - 80
TEDDER, T.F. ET AL., J, IMMUNOL., vol. 135, no. 2, 1985, pages 973 - 979
TEDDER, T.F. ET AL., J. IMMUNOL., vol. 142, 1989, pages 2560 - 2568
TEDDER, T.F. ET AL., J. IMMUNOL., vol. 142, 1989, pages 2560 - 8
TEDDER, T.F. ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 85, 1988, pages 208 - 12
TEDDER, T.F. ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 85, 1988, pages 208 - 212
UMANA P ET AL: "Novel 3(rd) generation humanized type IICD20 antibody with glycoengineered fc and modified elbow hinge for enhanced ADCC and superior apoptosis induction", BLOOD, AMERICAN SOCIETY OF HEMATOLOGY, US, vol. 108, no. 11, PART 1, 9 December 2006 (2006-12-09), pages 72A, XP008087672, ISSN: 0006-4971 *
UMANA PABLO ET AL.: "GA101, a novel humanized type IICD20 antibody with glycoengineered Fc and enhanced cell death induction, exhibits superior anti-tumour efficacy and superior tissue B-cell depletion in vivo", BLOOD, AMERICAN SOCIETY OF HEMATOLOGY, US, vol. 110, no. 11, abstract:2348, 2007, XP002559271, ISSN: 0006-4971 *
UMANA, P. ET AL., NATURE BIOTECHNOL., vol. 17, 1999, pages 176 - 180
VALENTINE, M.A. ET AL., J. BIOL. CHEM., vol. 264, 1989, pages 11282 - 11287
VALENTINE, M.A. ET AL., J. BIOL. CHEM., vol. 264, no. 19, 1989, pages 11282 - 11287
VAN DIJK, M.A.; VAN DE WINKEL, J.G., CURR. OPIN. PHARMACOL., vol. 5, 2001, pages 368 - 374
WRIGHT, A.; MONISON, S.L., TRENDS BIOTECH., vol. 15, 1997, pages 26 - 32
WRIGHT, A.; MORRISON, S.L., TRENDS BIOTECH., vol. 15, 1997, pages 26 - 32
WRIGHT, A.; MORRISON, S.L., TRENDS BIOTECHNOL., vol. 15, 1997, pages 26 - 32

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